Molecular pathways and animal models of tetralogy of fallot and double outlet right ventricle

Abstract

Tetralogy of Fallot and double outlet right ventricle are outflow tract (OFT) alignment defects situated on a continuous disease spectrum. A myriad of upstream causes can impact on ventriculoarterial alignment that can be summarized as defects in either (1) OFT elongation during looping morphogenesis or (2) OFT remodeling during cardiac septation. Embryological processes underlying these two developmental steps include deployment of second heart field cardiac progenitor cells, establishment and transmission of embryonic left/right information driving OFT rotation, and OFT cushion and valve morphogenesis. The formation and remodeling of pulmonary trunk infundibular myocardium are critical components of both steps. Importantly, OFT alignment is mechanistically distinct from neural crest-driven OFT septation, although neural crest cells impact indirectly on alignment through their role in modulating signaling during SHF development. As yet poorly understood non-genetic causes of alignment defects that impact the above processes include hemodynamic changes, the uterine environment, and stochastic events. The heterogeneity of causes converging on alignment defects characterizes the OFT as a hotspot of congenital heart defects.